Use of heterocyclic amino-alcohol compounds for treatment of CNS diseases

• US 5,462,965 A
• Filed: 12/07/1992
• Issued: 10/31/1995
• Est. Priority Date: 08/13/1990
• Status: Expired due to Fees

• Current Assignee: GD Searle & Company
• Original Assignee: GD Searle LLC (Pfizer Inc.)
• Inventors: Jarrott, Bevyn, Roba, Joseph L., Beart, Philip M., Gillet, Claude L., Rafferty, Michael F.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US07/949,815
• Time in Patent Office: 1,058 Days
• Field of Search: 514/649, 514/650, 514/653, 514/233.5, 514/238.8, 514/253, 514/317, 514/324, 514/392, 514/422, 514/431, 514/432, 514/416, 514/443, 514/456, 514/469, 514/649, 514/650 , 514/653
• US Class Current: 514/443
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/385 having two or more sulfur atoms in the same ring
• CPC Class Codes: A61K 31/39 having oxygen in the same ring
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A class of heterocyclic amino-alcohol compounds is described for treatment of CNS-related diseases, namely, for use as a neuroprotective agent, to reduce neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia which typically follows stroke, myocardial infarct, perinatal asphyxia, or hypoglycemic events. Other examples of treatable CNS-related diseases include neurodegenerative diseases such as Parkinson'"'"'s disease, Huntington'"'"'s chorea and Alzheimer'"'"'s disease, and also psychotic disorders such as schizophrenia. The treatment includes administration of a compound of this class alone or in a composition in an amount effective as a mediator to alter excitatory actions at the NMDA excitatory amino acid receptor complex. A compound of this class of specific interest is the following: ##STR1##

Claims

1. A method to treat the neuropathological consequences of neurotoxic injury or neurodegenerative disease mediated by an NMDA receptor in a subject, which method comprises administering to said subject a therapeutically-effective amount of a compound of Formula I:

##STR191## wherein X is selected from oxygen atom, sulfur atom, --CH₂ -- and --NH--;

wherein Y is selected from --CH₂ -- and --NH--;

wherein n is a number selected from one through three, inclusive;

wherein R¹ is selected from hydrido, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, phenyl and carboxyl;

wherein R² is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl and cyctoalkylalkyl;

wherein each of R³ and R⁴ is independently selected from hydrido, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, phenyl, phenylalkyl, diphenylalkyl, alkylphenyl, alkylphenylalkyl, halophenyl, halophenylalkyl, phenoxyalkyl, halophenoxyalkyl, alkoxyphenoxyalkyl, cyanophenoxyalkyl, benzyloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonylalkyl, phenylthioalkyl, alkylcarbonylaminophenylalkyl, halophenylcarbonylalkyl, halobenzylcarbonylalkyl, alkylcarbonylphenoxyalkyl, alkoxycarbonylphenoxyalkyl, alkylphenoxyalkyl, alkenylalkyl, alkynylalkyl, alkynylalkyloxyalkyl, polycycloalkyl, saturated or partially unsaturated heterocyclic, saturated or partially unsaturated heterocyclicalkyl, heteroarylalkyl and heteroaryloxyalkyl;

wherein R³ and R⁴ may be taken together to form a saturated or partially unsaturated heterocyclic group or a heteroaryl group, either of which groups may be further substituted, said groups selected from alkylphenylpiperidinyl, morpholino, phenylmorpholino, alkylmorpholino, 1-alkyl-2-phenylmorpholino, phenylalkylpiperidinyl, phenylpiperidinyl, phenylalkylpyrrolidinyl and phenylalkylpiperazinyl;

wherein R⁵ is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl and phenyl;

wherein R⁶ is selected from hydrido, alkanoyl and cycloalkanoyl;

and wherein any of the foregoing R¹ -R⁶ radicals may be further substituted at a substitutable position with a radical selected from alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkenylalkyl, alkoxyalkyl, hydroxyalkyl, oxo, cyano, halo, phenyl and phenylalkyl;

or a pharmaceutically-acceptable salt thereof.

2. The method of claim 1 wherein said neurotoxic injury is associated with stroke.

3. The method of claim 1 wherein said neurotoxic injury is associated with myocardial infarction.

4. The method of claim 1 wherein said neurotoxic injury is associated with perinatal asphyxia.

5. The method of claim 1 wherein said neurotoxic injury is associated with head trauma.

6. The method of claim 1 wherein said neurotoxic injury is associated with hypoglycemia.

7. The method of claim 1 wherein said neurotoxic injury is associated with epilepsy.

8. The method of claim 1 wherein said neurotoxic injury is associated with septicemia.

9. The method of claim 1 wherein said neuropathological consequences are from a neurodegenerative disease.